Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a compound derived from plants of the Solanacea family, commonly known as hot red peppers. Capsaicin has been utilized over the last two decades to study the neurophysiology and pharmacology of pain, as well as for the treatment of certain types of neuropathies and skin disorders. Such use is disclosed, for example, in U.S. Pat. No. 4,486,450, issued Dec. 4, 1984, and entitled "Method Of Treating Psoriatic Skil And Composition," and U.S. Pat. No. 4,536,404, issued Aug. 20, 1985, and entitled "Method And Composition For Treating Post-Herpetic Neuralgia;" both patents issued to the applicant herein.
While capsaicin is useful in treating painful neurological and other disorders, its utility has been limited by a troublesome adverse reaction which almost invariably accompanies its use. This reaction is a localized stinging and burning sensation, which can be quite severe, on application of capsaicin topically to skin or mucous membranes or on injection into tissues such as the dermis, the cerebrospinal canal or into blood vessels.
Attempts to reduce or eliminate this adverse effect have had only limited success, and include the incorporation of an anesthetic into the formulation. Since the stinging and burning have been thought to be directly linked to capsaicin's effects on neuropeptides in nerves, and these capsaicin effects on neuropeptides are thought to be crucial to capsaicin's efficacy in relieving pain, it has been considered impossible to significantly reduce the stinging and burning without greatly reducing or eliminating capsaicin's effectiveness.
When capsaicin is extracted from the pepper plant, such extracts contain a number of other compounds similar in structure to capsaicin, but with different properties. A number of these compounds, known as capsinoids, have been evaluated for their ability to deplete neuropeptides. None of these capsinoids has been found to be as effective as capsaicin in depleting the neuropeptides, and all of those known to have any measurable neuropeptide depleting activity also cause an uncomfortable degree of burning and stinging.
It is thus an object of the invention to provide methods of treating painful, inflammatory, or allergic disorders without the adverse stinging and burning associated with the use of capsaicin.
It is still another object of the invention to provide pharmaceutically acceptable compositions suitable for use in the inventive method.
In an attempt to discover a capsinoid which might be able to be more cheaply substituted for capsaicin in medicinal formulations, applicant has evaluated cis-8-methyl-N-vanillyl-6-nonenamide, a stereoisomer of capsaicin. The existence of this capsinoid in small quantities in pepper extracts has been known for some time. It has, however, always been believed that, like the other capsinoids, cis-8-methyl-N-vanillyl-6-nonenamide lacked significant neuropeptide depleting activity.
Applicant has discovered, quite surprisingly, that cis-8-methyl-N-vanillyl-6-nonenamide is much more potent as a depleter of neuropeptides from sensory nerves than is capsaicin. Even more surprisingly, applicant has discovered that cis-8-methyl-N-vanillyl-6-nonenamide produced such neuropeptide depletion without producing the extreme degree of burning or stinging produced by capsaicin. The invention therefore includes compositions of cis-8-methyl-N-vanillyl-6-nonenamide incorporated in topical formulations suitable for application to skin or mucous membranes, which compositions can produce in both man and animals pronounced analgesia without the pronounced irritant effects of capsaicin. The invention also includes compositions of cis-8-methyl-N-vanillyl-6-nonenamide incorporated into other medicinal formulations suitable for injection, oral ingestion, pulmonary inhalation, rectal administration or ophthalmic or nasal administration. When incorporated into such medicinal formulations, cis-8-methyl-N-vanillyl-6-nonenamide is substantially more potent than capsaicin and will produce less local irritation in the form of burning, stinging or vasodilitation than capsaicin. The invention also includes methods of using the inventive compositions to treat painful, inflammatory, or allergic disorders.